In the 1960s, the US Atomic Energy Commission initiated a research program on the health and mortality of US nuclear workers. From the outset, it was noted that facility-specific cohort studies were unlikely to include sufficient numbers of workers to provide statistically precise epidemiological findings;however, combining data across facilities could allow an investigator to study associations in a large population of nuclear workers. We propose to conduct a pooled analysis of US worker data for employees of 5 major facilities selected based on cohort size, availability of demographic and employment history information, and completeness of radiation monitoring data: Oak Ridge National Laboratory, Savannah River Site, Hanford site, Idaho National Laboratory, and Portsmouth Naval Shipyard. An update of vital status follow-up of each cohort has been conducted recently, making the proposed analysis feasible. The proposed combined study of US workers will permit us to address outstanding questions regarding variation in radiation risks with time-since-exposure and age-at-exposure, as well as variation in radiation risks by type of cancer. We propose to employ state-of-the- art methods to minimize bias due to confounding, sensitivity analyses to assess the impact of exposure misclassification, and innovative regression models to assess effect measure modification and between-cohort heterogeneity in radiation risks. Moreover, a causal interpretation of epidemiological study findings is strengthened by evidence of reproducibility and consistency. Therefore, we propose to empirically assess the consistency of results derived from US nuclear worker data with results derived from UK and French nuclear worker cohorts, two nations that also developed large nuclear programs. A novel hierarchical regression approach will be used to assess the consistency of findings between US, UK, and French workers in a joint analysis that employs comparable analytical methods for each cohort. If pooling data from these 3 countries is appropriate, an international combined analysis will be conducted in order to derive the most precise radiation risk estimates for nuclear workers reported to-date. The proposed international combined analysis will have more than twice the statistical power of any prior epidemiological study of cancer among nuclear workers. The findings of this research project are expected to have substantial impact on discussions regarding occupational radiation risks and radiation protection. PUBLIC HEALTH RELEVANCE: There has not been a report on a combined cohort analysis of associations between radiation exposure and all cancer mortality among US nuclear workers in over two decades. We propose to conduct a pooled analysis of recently-updated US nuclear worker data for Oak Ridge National Laboratory, Savannah River Site, Hanford site, Idaho National Laboratory, and Portsmouth Naval Shipyard. Updated data are available for each of these cohorts providing the basis for a major update of US combined nuclear worker cohort analyses. The study will address outstanding questions regarding latency effects, site specific cancer risks, and modification by age at exposure. In order to strengthen interpretation of these analyses, we propose to assess the consistency of findings derived from US nuclear worker data with those derived from UK and French nuclear worker cohorts and, if appropriate, to conduct an international pooled analysis of these data. This ambitious study draws upon large existing repositories of nuclear worker data. The findings of the proposed study are expected to have substantial impact on understanding of occupational radiation risks and the adequacy of current radiation protection standards.